Combination controller and patch for the photodynamic therapy of dermal lesion

ABSTRACT

Combination controller and patch for photodynamic therapy of a dermal lesion located at a dermal treatment site on skin including stratum corneum, the controller is optically connected to the patch and the patch includes hydrogel containing hydration agent and photopharmaceutical, the patch covers the site and the hydrogel engages and couples the hydration agent to the stratum corneum to hydrate and soften the stratum corneum to enhance its optical transmissiveness to facilitate the transmission of light therethrough and to enhance its chemical transmissiveness to facilitate the transmission therethrough of the photopharmaceutical for treatment of the dermal lesion, light delivery apparatus are included in the patch for receiving light from the controller and for delivering light through the hydrogel and the hydrated stratum corneum to the site to photoactivate the photopharmaceutical at the site to treat the dermal lesion.

BACKGROUND OF THE INVENTION

This invention relates generally to combination controller and patch forthe photodynamic therapy (PDT) of dermal lesion such as for exampleactinic keratosis, basal carcinoma and psoriasis. More particularly,this invention relates to a portable combination controller and patchfor applying photodynamic therapy to a dermal lesion using a light orphotoactivated photopharmaceutical wherein the amount ofphotopharmaceutical activation is patient controllable for patientcomfort.

Bodies, sheet or layer forms, of hydrogel or hydrogel materials,particularly transparent hydrogel or hydrogel materials, are well knownin the medical field and may comprise, for example, a polyvinyl alcoholwith a water matrix; some of these transparent hydrogel or hydrogelmaterials are castable and may be cast into intimate contact with otherdevices. They have been widely adapted to such applications asdiagnostic electrodes (for EKG), wound care dressings, and transdermaldelivery devices for systemic delivery of pharmaceutical agents. Thebiocompatability of this class of materials is well established forextended contact with dermal structures. Much of the prior art inmedical applications for hydrogel or hydrogel materials teaches devicesand methods for electrical conductivity enhancement. Critical in usinghydrogel in many medical applications, such as an electrical interface,is the ability of the hydrogel to form intimate physical contact withskin or dermal structures. U.S. Pat. No. 5,143,071 issued to Keusch etal. on Sep. 1, 1992, cites an extensive list and description of priorart hydrogels suitable for this purpose, and this patent is incorporatedherein by reference.

A concurrent body of prior art embraces hydrogels or hydrocolloids, aswound dressings and dressings impregnated with pharmaceutical compounds;representative of this prior art is U.S. Pat. No. 5,156,601 to Lorenzeet al. Further, the work of Gombotz et al., Proc. Intl. Symp. Cont. Rel.Bioact. Mtl., Vol. 19, 1992, describes the rapid release of complexcompounds from hydrogels to skin or dermal structures.

U.S. Pat. No. 5,079,262 issued to Kennedy et al. discloses a method ofdetection and treatment of malignant and non-malignant lesions utilizing5-aminolevulinic acid. The acid is administered to a patient in anamount sufficient to induce synthesis of protoporphyrin IX in thelesions, followed by exposure of the treated lesions to aphotoactivating light in the range 350-640 nm. The acid is taught to beadministered to the patient orally, topically or by injection.

None of the prior art references teach or suggest the photodynamictherapy of dermal lesions using hydrogel as an optical, chemical orfluidic coupling agent for light and photopharmaceutical to skin. Sinceits first reported clinical use at the turn of the century, photodynamictherapy has been accomplished using light projected to the dermaltreatment site from sources at some distance from the site. Modernphotodynamic therapy (from 1978 onwards) has developed light deliveryprotocols using artificial sources such as tungsten halogen, or xenonarc lamps with wavelength filtration to activate photopharmaceuticals.All of the above light sources have been used in projective, fieldilluminating devices that flood the target treatment field or site inthe treatment of superficial cutaneous lesions with light containing awavelength designed to activate the photopharmaceutical. Thesereferences generally teach that the dosimetry of applied photodynamictherapy can be controlled and varied by varying the intensity and/orduration of the photoactivating light applied to a photopharmaceuticalperforming photodynamic therapy.

In the case of the tungsten and xenon-arc sources, extensive filtrationof the available light flux is essential to restrict the deliveredenergy to appropriate wavelengths that photoactivate thephotopharmaceutical in the target dermal structures. Colored glass orinterference filters used with these sources transmit some portion ofunwanted wavelengths, notably in the infrared region, and can causethermal effects that may mask the effect of photoactivity with anundesirable heating effect that also preferentially damages malignanttissue. High-power surgical lasers, even when de-focussed, also caninduce undesirable thermal effects. The work of Svaasland,Photochem/Photobiol. 1985, measured this effect and its impact on PDTprotocols.

Dosmetry of delivered photodynamically effective light to a dermaltreatment site is extremely difficult using current projective optics.Mathematical modeling of skin optics has been a slow and difficultprocess. Recent publications by Van Gemert et al., IEEE Trans. Biomed.Eng., Vol. 36;12, 1989, critically reviewed the prior work and presentsa 4-layer model of light-dermal tissue interaction; this publication isincorporated herein by reference. Van Gemert et al. elaborates on theadvantages and effectiveness of the diffusion model of light transportin tissue, which depends upon the efficient coupling of the externallyapplied light to the target tissue. A later publication by R. RoxAnderson, Optics of the Skin, Clinical Photomedicine, DekkerPublication, 1993, reviews the two basic processes which govern theoptics or behavior of light in skin, namely, light absorption and lightscattering; this publication is incorporated herein by reference.

It has been found that an efficient and practical means of establishingthe diffusion conditions of light transport is to provide transparentcoupling means that is in intimate contact with the skin containingdermal lesions on one surface and with the light source on its oppositesurface. Under these conditions reflective losses are reduced, anddelivered optical energy is much more efficiently transmitted into thetarget region.

The stratum corneum present at a dermal treatment site on the skin of aperson is a formidable barrier to transport (transmission, penetrabilityor permeability) of light into the deeper structures of the skin wheredermal lesions typically reside, in whole or in part. The layeredplate-light corneocytes comprising the stratum corneum constitute anefficient reflective optical surface which reflects nearly all light inthe visible spectrum. There is some transmission in the region of 590 to700 nanometers. Photopharmaceuticals are formulated to be activated bylight energy in this region. Penetration depth is in the region of 1-3mm from the dry corneocyte surface. It has been discovered that theinterposition of a flexible transparent hydrogel coupling layer betweena monochromatic plate or sheet-formed light source and the skin surfaceconstitutes a new and more efficient delivery of activating opticalenergy to target dermal lesions for photodynamic therapy; particularlywhere the monochromatic light source delivers light at the specificwavelength at which the photopharmaceutical is photoactivated.

There are other substantial benefits that attend the use of anintimately contactive hydrogel coupling layer. Because hydrogels aretypically 60 to 90% water, hydration of the stratum corneum occursrapidly following contact with the hydrogel sheet. This hydration has asubstantial optical transparency, or optical transmissiveness, enhancingeffect, allowing more light to pass through the stratum corneum.Although the mechanism of this optical transparency has not beenextensively studied, it is thought to result from a reduction of thelight reflectivity of the stratum corneum through softening of thecorneocytes by a solvent or plasticizing action. Castable transparenthydrogels are also known to the art which may be cast into intimatephysical and optical contact with, for example, a source of light.

It is well established in the literature of chemical transport throughthe skin that hydration can enhance the chemical transparency,transmissiveness, passage or transport of pharmaceuticals through thestratum corneum. A review of discussion of this enhanced transport underhydrated conditions is found in Ghosh et al., pharmaceutical Tech.,April 1993, which publication is incorporated herein by reference.

It follows that there are two key requirements of PDT to dermalstructures where the protocol requires topical application of thephotopharmaceutical. Transport of the photopharmaceutical into targettissue, and subsequent light activation of the photopharmaceutical atthe target tissue, these can be more efficiently accomplished using thediffusion route for both the drug and the activation optical energy.

It has been found that a hydrogel coupling layer serves the dual purposeof establishing conditions for the optical energy diffusion into skintissue and photopharmaceutical compound diffusion or other introductioninto skin tissue, by the intercellular or transcellular routes; however,it will be understood that the introduction of the photopharmaceuticalfrom the hydrogel into the hydrated skin or through the hydrated stratumcorneum, depending on the specific photopharmaceutical used, can be bythe above-noted diffusion, or by absorption, or by other mechanismconstituting chemical permeation or penetration of the hydrated skin orstratum corneum. A third optical advantage of a transparent transporthydrogel is that it can remain in place after PDT exposure, as aprotective dressing.

In the preferred embodiment of this invention, a transparent hydrogelserves as a transport or reservoir of a hydration agent andphotopharmaceutical and which hydrogel rapidly releases thephotopharmaceutical to the skin tissue. For purposes of photodynamictherapy, rapid delivery is desirable. This contrasts with prior arttransdermal devices for non-PDT drug delivery which seek to provide muchslower release kinetics for system absorption. Further, in the presentinvention, the photodynamic therapy is localized to a dermal treatmentsite defined by a cover, container or patch covering the site where thedermal lesion is located and the light necessary to activate thephotopharmaceutical is delivered only to the dermal treatment site. Itis thus advantageous to rapidly deliver the light activatedphotopharmaceutical doses to skin tissue, and dermal lesion, and thendeliver the light dose to initiate its biological activity to treat thedermal lesion.

The intimate hydrogel contact established at the skin surface of thetreatment site forms both a fluid or fluidic coupling for thephotopharmaceutical and an optical or optic coupling for thephotoactivating light. In the case of the chemical or fluidic coupling,the water contained in the hydrogel matrix begins to solubilize thestratum corneum, hydrating this normally dry layer, and forms an avenueof exchange between the hydrogel and the dermal lesion. Hydrationenhances both intracellular and transcellular pathways. Uponestablishment of these pathways, transport of the photopharmaceutical totarget tissue or dermal lesion commences.

The effect of hydration on fluid transport across the stratum corneumlayer is substantial. Normally this structure contains 10-15% water.Hydrated stratum corneum can retain up to 50% water and the normal lightdiffusion coefficient of the hydrated stratum corneum can increaseten-fold.

The effect of hydration on optical coupling of light into skin tissue isalso substantial, but is sustainable only with the contact of thetransparent hydrogel to both the skin tissue and the light source. Inthe preferred embodiment a fiber optic panel comprising a plurality offiber optic strands is used as a light delivery source to activate thephotopharmaceutical, and hydrogel contact with the fiber optic strandsis efficient because at manufacture the hydrogel is cast against, andplaced in intimate physical contact with, the fiber optic strands andconforms to the regular geometry of these strands achieving intimateoptical coupling. The formation of the hydrogel to skin surface junctureoccurs at the point of engagement of the hydrogel to the skin surface.The physical characteristics of the hydrogel necessary to establishintimate skin contact are those described for electrode contact in theprior art references, cited above. Similar characteristics are requiredfor performing PDT with the present invention, with the added hydrogelattributes of light transmission and hydration of the skin.

The mechanical changes hydration produces in the stratum corneum layerhave substantial impact on the optical coupling efficiency of externallyapplied light in the red region of the spectrum. The ultra-structure ofthe stratum corneum is an array of flattened essentially dead cellswhich are constantly being shed in a natural process of skin surfacerenewal. This results in a very uneven, dry, and highly light reflectivelayer or barrier to light penetration or transmission. Hydration bycontact with emollients and oil-based unguents confers an improvedsurface but the effect is transitory under projected opticalillumination schemes that, through surface heating, rapidly degrade thehydration effect by drying out of the target region. Thus thoughtopically applied agents for PDT may briefly induce an opticalimprovement, it rarely persists through the projected light illuminationphase if surface heating occurs during illumination.

This is in marked contrast with the present invention, where thehydrogel remains in place during the light dosage and serves as ahydration agent and photopharmaceutical reservoir or transport means,and conduit and coupling for both light and fluidized agents to thetarget tissue or dermal treatment site during all phases of photodynamictherapy of a dermal lesion.

It is the object of the present invention to provide a new and improvedcombination controller and patch for the photodynamic therapy of dermallesion and which, in the preferred embodiment, permits the patientundergoing photodynamic therapy to control or vary the appliedphotodynamic therapy for the patient's comfort and to eliminate, orsubstantially eliminate, patient discomfort and even pain.

SUMMARY OF THE INVENTION

Combination controller and patch for photodynamic therapy of a dermallesion located at a dermal treatment site on skin including stratumcorneum at the site, the controller is optically connected to the patchand the patch includes transparent coupling (e.g. hydrogel) for coveringthe dermal treatment site and which contains hydration agent andphotopharmaceutical, the transparent coupling couples the hydrationagent to the stratum corneum to hydrate and soften the stratum corneumto enhance its optical transmissiveness to facilitate the transmissionof light therethrough and to enhance its chemical transmissiveness tofacilitate the transmission therethrough of the photopharmaceutical tothe dermal treatment site for treatment of the dermal lesion, a sourceof light delivery is included in the patch and receives optical energyfrom the controller and delivers the light through the transparentcoupling and the hydrated stratum corneum to the photopharmaceutical atthe site to photoactivate the photopharmaceutical to biologically engageand treat the dermal lesion.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatical illustration, substantially in cross-section,illustrating prior art photodynamic therapy of a dermal lesion usingprojection optics;

FIG. 2 is a diagrammatical illustration, substantially in cross-section,illustrating a first embodiment of the patch the present invention;

FIG. 2A is a partial cross-sectional view of the cover of the patch ofthe present invention and which illustrates that the internal surface ofthe cover may be provided with a suitable light reflecting layer orcoating;

FIG. 3 is a perspective cut away diagrammatical illustration of thefirst embodiment of the patch shown in situ over a dermal treatmentsite;

FIG. 3A is a partial perspective view of an optical fiber strandillustrating diagrammatically the lateral or radial exiting of laserlight;

FIG. 4 is an exploded view, partially in cross-section, illustrating asecond embodiment of the patch of the present invention;

FIG. 5 is a perspective diagrammatical illustration, substantially incross-section, illustrating the second embodiment of the patch shown insitu over a dermal treatment site and also showing connection to a laserdiode;

FIG. 6 is a diagrammatical perspective view, partially in cross-section,illustrating a procedure tray containing the components of the firstembodiment article of manufacture of the present invention illustratedin FIGS. 2 and 3;

FIG. 7 is a perspective view, in partial cutaway, illustrating anembodiment of the combination controller and patch of the presentinvention for applying photodynamic therapy to dermal lesions;

FIG. 8 is a general block diagram of computer means which may beincluded in the controller of the present invention and a general blockdiagram of a patch of the present invention; and

FIG. 9 is a flow chart of the computer program stored in the programmedlogic array which is executed without patient, or attending physician orclinician, intervention; and

FIG. 10 is a flow chart of the computer program also stored in theprogram logic array which is executed with patient, or attendingphysician or clinician, intervention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates prior art photodynamic therapy of dermal lesions 10located in a person's skin indicated by general numerical designation12, which skin includes the stratum corneum 14. [It will be understoodthat the dermal lesions 10 are illustrated diagrammatically in FIG. 1,and in FIGS. 2, 3 and 5 referred to below, by the darkest spots shown inthe skin 12. It will be further generally understood that the dermallesions 10 are generally located under the stratum corneum 14 or withinthe skin 12 or can extend partly outwardly of the skin as illustrated inFIG. 1.] Projective light source 13 directs light, indicated by arrows16, onto the skin 12 and, as noted generally above, the stratum corneum14 scatters the light with substantial portions of the light, asindicated by arrow 17, being reflected away from the stratum corneum 14and thereby not initiating any photodynamic therapy. However, as furthernoted above, red light within the light 16 can penetrate the skin 12 to3-4 mm. The projective light source 13 is typically either a filteredincandescent source or a laser and is normally arranged to project thelight 16 perpendicular to the skin 12 and corneum 14. It will be furtherunderstood from FIG. 1 that the dermal treatment site, indicatedgenerally by numerical designation 18, is generally not well defined indistinction to the dermal treatment site produced by the presentinvention described below and illustrated particularly in FIG. 2.

Referring to FIG. 2, the first embodiment of a patch of the presentinvention, particularly useful for use with the controller 80 of thepresent invention shown in FIG. 7 and described blow, is indicated bygeneral numerical designation 20. Patch 20 includes a cover 22, whichmay be also referred to as a container, and may be made, for example, ofMylar and suitably formed into the shape shown such as for example byvacuum forming. It will be noted that the lower portion of the cover 22may be provided with an outwardly extending flange or peripheral portion23 circumscribing the lower cover portion, and which peripheral portion23 may be provided with a suitable layer of adhesive 24, of the typeknown to the art to be compatible with the human skin, for sealinglyengaging the skin 12 to seal the cover 22 to the skin and define andcover a dermal treatment site indicated by general numerical designation25; the flange or peripheral portion 23 and adhesive layer 24 are betterseen in FIG. 2A. It will be noted that in use of the patch 20 of thepresent invention illustrated in FIG. 2, the dermal treatment site 25 iscomparatively narrowly and well defined as contrasted to the open andcomparatively poorly defined prior art dermal treatment site 18illustrated in FIG. 1. The cover 22 provides an internal chamber 22A,better seen in FIG. 2A, opposite the dermal treatment site 25 and a bodyor layer of transparent hydrogel 26 is received and resides within thechamber 25. Transparent hydrogel 26 may be a transparent hydrogel of thetype described above and may be, for example, a polyvinyl alcohol havinga water matrix which water serves as a hydration agent in the presentinvention; the water or hydration agent is illustrated diagrammaticallyin FIG. 2 by circles 27. In addition to containing the water orhydration agent 27, the transparent hydrogel 26 includes a suitablephotopharmaceutical for treating the dermal lesion 10 and whichphotopharmaceutical is illustrated diagrammatically in FIG. 2 by thecircles 28; the photopharmaceutical 28 may be introduced into thetransparent hydrogel 26 by absorption. The photopharmaceutical 28 maybe, for example, photopharmaceutical 5-ALA available from the SigmaChemical Company, St. Louis, Mo., and which photopharmaceutical is madephotoactive by red light at a wavelength of substantially 635 nm.

The patch 20, FIG. 2, further includes a light delivery source indicatedby general numerical designation 30 and which may be an optic laserlight-emitting panel available from Lasermax, Inc., of Rochester, N.Y.which emits monochromatic red light having a wavelength of substantially635 nm so as to be photoactively compatible with and matched to thephotoactive wavelength of the photopharmaceutical 28 contained in thetransparent hydrogel 26. The optic laser light-emitting panel 30includes a plurality of optical fiber strands 31 indicated in transversecross-section by the linearly aligned circles shown in FIG. 2 and whichstrands 31 may be better seen in cylindrical perspective view in FIG. 3.Referring to FIG. 2A, the cover 22 includes an internal surface 34 whichmay be provided with a suitable layer or coating of reflective material35 which may be a layer of suitable reflective foil suitably adhesed tothe internal surface 34, or thermally staked thereto, or may be asuitable reflective coating provided by a suitable deposition process;reflective layer 35 is not shown in FIG. 2 since it is relatively thinas compared to the cover 22 but it will be understood that suchreflective layer is present in patch 20 of FIG. 2. The optic laserlight-emitting panel 30 resides within the chamber 25 and may besuitably secured to the cover 22, and to or through the reflective layer35, by a suitable adhesive or by suitable thermal staking. Thetransparent hydrogel 26 is a castable hydrogel and is cast into intimatephysical and optical contact with the panel 30.

Referring to FIG. 3, it will be understood that the strands of opticalfibers 31 of the optic laser light-emitting panel 30 are actually theends or end portions of the optical fibers contained in the opticalfiber bundle 36 which terminate in a suitable optical fiber connector37; as shown in FIG. 4, the cover 22 is provided with a suitably sizedopening 51 for admitting the optical fiber bundle 36 therethrough.Connector 37 is for being connected to a suitable laser diode 40 forproducing, in the preferred embodiment, monochromatic red lightindicated by the arrows 42 having a wavelength of substantially 635 nm;the laser diode 36 may be, for example, a told 635 available fromToshiba Optical Systems. The laser light 42 is transmitted or ducted tothe optical strands 31, through the optical bundle 36 and, as may beunderstood from FIG. 3A, the optical fiber strands 31 are provided withside openings or lateral notches 39 which cause or permit the laserlight 42 (FIG. 3) to be emitted at a number of angles from the sides ofthe strands 31 but which light is ultimately reflected by the reflectivelayer or surface 35 (FIG. 2A) and caused to ultimately impinge upon thestratum corneum 15 and skin 12. As may be noted in FIG. 2, the laserlight, as indicated by the arrows 29, is reflected off the reflectivesurface (FIG. 2A) and transmitted through the transparent hydrogel 26.

Upon patch 20, FIGS. 2 and 3, being sealingly engaged to the skin 12 andstratum corneum 14 as illustrated in FIGS. 2 and 3 and described above,the water or hydration agent 27 contained in the transparent hydrogel 26engages the stratum corneum 14 and immediately begins to hydrate andsoften the stratum corneum to enhance its optical transparency ortransmissiveness to facilitate the transmission of the laser light 37therethrough and to enhance its chemical transparency ortransmissiveness to facilitate the transmission therethrough of thephotopharmaceutical 28 and into the dermal treatment site 25 containingthe dermal lesion 10. The laser light 42 (FIG. 3) is introduced into thedermal treatment site 25 and illuminates the site by light diffusionwhich photoactivates the photopharmaceutical 28 to initiate itsbiological activity and to cause the photoactivated photopharmaceuticalto biologically engage and treat the dermal lesion 10. After suchtreatment, as noted generally above, the cover 22 of the patch 20 mayremain in place after the photodynamic therapy as a temporary protectivedressing for the dermal treatment site 25. It will be further understoodthat a biologically sufficient quantity of photopharmaceutical isintroduced into the hydrogel to accomplish treatment of the dermallesion.

Referring now to FIGS. 4 and 5, a second embodiment of a patch of thepresent invention, particularly useful in combination with thecontroller 80 of the present invention shown in FIG. 7 and describedbelow, is shown and indicated by general numerical designation 20A. Thestructural elements in patch 20A which are the same, or substantiallythe same, as the corresponding structural elements in patch 20 of FIGS.2 and 3, are given the same numerical designation as the elements inFIGS. 2 and 3. It will be generally understood that patch 20A appliesphotodynamic therapy to dermal lesions 10, FIG. 5, in substantially thesame manner as patch 20 of FIGS. 2 and 3. However, in the embodiment20A, the transparent hydrogel 26A while including the water or hydratingagent indicated by circles 27 in FIG. 2, does not contain thephotopharmaceutical indicated by circles 28 in FIG. 2. Patch 20A furtherincludes a second layer or sheet of transparent hydrogel 50 which issmaller in size or thickness than transparent hydrogel 26A and which,although containing a water matrix in which the photopharmaceutical iscontained, is highly dehydrated as compared to the transparent hydrogel26A. The relatively highly dehydrated state of the transparent hydrogel50 permits the transparent hydrogel 50 to be cut and trimmed, such as bya pair of scissors 51, into a body of hydrogel 54 having a size muchsmaller than the transparent hydrogel 26A and shaped into substantiallythe same shape as the underlying dermal lesion 10, FIG. 5. As is known,the photopharmaceutical contained in the transparent hydrogel 50 istoxic, typically acidic, and its application to the skin of a patientcan be at least somewhat discomforting or even painful. It has beendiscovered that by reducing the size of the hydrogel containing thephotopharmaceutical a reduced but still biologically sufficient quantityof photopharmaceutical can be applied photodynamically to the patientbut with reduced discomfort. This also facilitates a photopharmaceuticalprofile that minimizes the application of the photopharmaceutical tohealthy tissue at the dermal treatment site 25, FIG. 5, yet allows thecontrolled delivery of photoactivating light to the entire dermaltreatment site 25. In application, and in practice of the photodynamictherapy, the trimmed hydrogel 54 resides within the cover 22intermediate the transparent hydrogel 26A and the treatment site 25 asmay be noted particularly from FIG. 5. The transparent hydrogel 26A andtrimmed hydrogel body 54 function in substantially the same manner asthe single layer of transparent hydrogel 26 in patch 20 of FIGS. 2 and 3to apply photodynamic therapy to the dermal lesion 10.

A procedure tray is indicated by general numerical designation 60.Procedure tray 60 is a single use procedure tray and may be suitablythermoformed from a suitable plastic such as polypropylene; it will befurther understood that the patches 20 and 20A of the present inventionare also single use patches. The tray is compartmentalized, as shown, toreceive, for example, the components or elements comprising the articleof manufacture 20 shown in FIGS. 2 and 3. The transparent hydrogel 26may be received within a moisture impervious foil or laminate pouch 61,the cover 22 and optic laser light emitting panel 30 may be received incompartments as shown also. The procedure tray 60 is sealed againstmoisture variation by a "peelable" foil sealing panel 63. The sealingpanel 28 is removed and the elements or components of the article ofmanufacture 20 are assembled as illustrated in FIGS. 2 and 3 andthereafter may be applied to the skin as described above and illustrateddiagrammatically in FIGS. 2 and 3.

Referring now to FIG. 7, combination controller and patch for applyingphotodynamic therapy to dermal lesion embodying the present invention isshown with the combination being indicated by general numericaldesignation 70. Combination 70 includes controller 72 and patch 20 shownin FIGS. 2 and 3 and described above, or in the alternative patch 20Ashown in FIGS. 4 and 5 and described above. It will be understood thatthe controller 72 and patch 20, or 20A, are of a size and weight thatthey can be conveniently carried by a patient receiving the photodynamictherapy. The controller 72 may be provided with a suitable loop 73through which a patient's belt may be inserted, or the controller 72 maybe provided with a suitable clip (not shown) for clipping the controllerto the patient's clothing.

Controller 72 includes a housing 74 which may be made of a suitableplastic suitably shaped into the configuration shown. Mounted to thehousing 74 is a source of optical energy 75 which may be, for example, asolid state diode laser of the type noted above and which, in apreferred embodiment, emits monochromatic red light having a wavelengthof substantially 635 nm. Suitable collimating optics or lens 76 aremounted to the housing intermediate the diode laser 75 and the patchconnector 37 for aligning and directing the optical energy or laserlight 77, sometimes referred to as light flux, into the connector 37 andthereby into the bundle of optic fibers 36 and to and out the sides ofthe optical fiber strands 31 of the panel 30 as described above. It willbe understood that the connector 37, as shown in FIGS. 3 and 5 anddescribed above, is disconnectable from the housing 74, and it will befurther understood that in the preferred embodiment of the presentinvention the patch 20 is a single use patch which may be disposed ofafter use; it will be further understood that the controller 72 is notdisposable but instead may be used numerous times with differentdisposable patches. A power supply 78, which may be a plurality ofsuitable batteries such as rechargeable batteries, is mounted to ahousing 74 to provide power to the solid state laser diode 75 and to thecomputer or processor indicated by general numerical designation 80.

Computer 80 is suitably mounted in the housing, such as by surfacemounting technology of the type known to the art, and includes themicroprocessor and clock 82 and program logic array 84 illustrated inblock diagram in FIG. 8; these components may be any one of severalsuitable components known to the art. The power supply 78 also providespower to the computer 80. A suitable liquid crystal display 85, FIG. 7,is suitably mounted to the housing 74 and is connected operably to themicroprocessor 82 as indicated diagrammatically in FIG. 8. It will beunderstood generally that the display 85 provides a visible indicationto a patient undergoing photodynamic therapy, or an attending clinicianor physician, of the treatment steps of the photodynamic therapy thatare being performed or their status. Generally, the patient, attendingphysician or clinician, operates the controller 72 to apply photodynamictherapy to the patient's dermal lesion through depression of thepower-on button 88. If desired, or required, a photodetector 93, may bemounted on the computer 82 and one or more optical fibers from thebundle 36 may be connected to the photodetector whereby the opticalenergy or laser light applied to the optical fiber strands 31 may besampled or monitored and suitable input provided from the photodetectorto the computer to provide a further control of the optical energy orlaser light applied to the patch 20 for photodynamic therapy asdescribed above.

Control, and varying of the photodynamic therapy applied to the dermallesion, may be under the control of the patient receiving thephotodynamic therapy or the attending clinician or physician and, moreparticularly, will be applied generally in accordance with thephotodynamic therapy dosage applied to the dermal treatment sitepursuant to a preprogrammed time and intensity profile coded into thecomputer 80 and more particularly as coded into the program logic array84, FIG. 8, pursuant to the computer program flow charts set forth inFIGS. 9 and 10. It will be understood that the flow charts set forth inFIGS. 9 and 10 will enable a computer programmer of ordinary skill inthe art to write and introduce a program into the program logic array84, in any one of several different computer programming languages, tocause the combination controller and patch of the present invention toapply photodynamic therapy to treat the dermal lesion in accordance withthe programmed instructions.

As noted above, photodynamic therapy applied to dermal lesion can causediscomfort and even pain to the patient and it will be furtherunderstood, and as noted above with regard to the incorporatedpublications of Van Gemert et al. and Anderson et al., incorporatedhereinabove, that the photodynamic therapy applied can be varied byvarying the intensity and/or duration of optical energy or light appliedto photoactivate the photopharmaceutical.

Referring again to FIG. 7, it will be noted that the controller 72includes the above-noted power-on button 88, and a start button 89, apower level up button 90 and a power level down button 91. These buttonsare also shown in FIG. 8 as being connected to the microprocessor andclock 82 of the computer 80. Upon the power-on button 88 beingdepressed, by the patient or an attending physician or clinician, thecontroller 70 under the control of the computer 80, and pursuant to theprogram stored in the programmed logic array 84 in accordance with theflow chart set forth in FIG. 9, will apply photodynamic therapy to thepatient's dermal lesion as described above with regard to patches 20 and20A. This program will run automatically in accordance with thedosimetry programmed into the computer in accordance with thepredetermined photodynamic treatment protocol determined by the programinstructions in the program logic array 84. If the patient experiencesdiscomfort, or even pain, pursuant to the automatically operatedphotodynamic treatment protocol, the patient, or attending physician orclinician, can intervene by depressing the start button 89, FIGS. 7 and8, which will cause the computer 80 to apply photodynamic therapythrough the patch 20 pursuant to the computer program stored in theprogram logic array 84 pursuant to the flow chart set forth in FIG. 10.If the patient experiences further discomfort, the patient, or attendingphysician or clinician, may depress the power level down button 91 todecrease the intensity and/or duration of the optical energy, or laserlight, applied to the photopharmaceutical thereby decreasing thephotoactivity of the photopharmaceutical and decreasing the patient'sdiscomfort. If the patient is not experiencing discomfort and desires toaccelerate the photodynamic therapy of the dermal lesion, the patient,attending physician or clinician, may depress the power level up button90 whereupon the computer 80, again under the control of the programmedlogic array 84 and the instructions programmed therein pursuant to FIG.10, will increase the intensity of the optical energy, or laser light,applied to the photopharmaceutical to increase its photoactivity untilthe patient again experiences discomfort whereupon the patient, orattending physician or clinician, may again depress the power level downbutton to reduce such discomfort.

It will be understood that the term photopharmaceutical as used hereinand in the appended claims means an agent which is itself aphotosensitizer or which is converted to a photosensitizer in the body.

It will be understood that many variations and modifications may be madein the present invention without departing from the spirit and the scopethereof.

What is claimed is:
 1. Apparatus for applying photodynamic therapy to a dermal lesion located at a dermal treatment site on the skin including stratum corneum, comprising:patch means for applying photodynamic therapy to the dermal lesion and including transparent coupling means containing at least one hydration agent, at least one photopharmaceutical, and optical energy delivery means for delivering optical energy to said patch means, said coupling means for coupling said hydration agent, said photopharmaceutical, and said optical energy to said dermal treatment site; control means for controlling the photodynamic therapy including a source of optical energy connected to said optical energy delivery means; said patch means for being secured to said skin over the dermal treatment site to cause said transparent optical coupling means to engage the stratum corneum to cause said hydration agent to hydrate the stratum corneum to enhance its optical transparency to the photopharmaceutical to permit the photopharmaceutical to pass therethrough and enter the treatment site and to enhance the optical transparency of the stratum corneum to facilitate the passage therethrough of said optical energy; and said optical energy delivery means for delivering said optical energy through said transparent coupling means and said hydrated stratum corneum to said photopharmaceutical at the dermal treatment site to photoactivate said photopharmaceutical to cause said photopharmaceutical to biologically engage and treat the dermal lesion.
 2. The apparatus according to claim 1 wherein said patch means includes cover means for covering the dermal treatment site provided with sealing means for sealing said cover means over the dermal treatment site, and wherein said transparent coupling means include transparent hydrogel means, including a water matrix, for providing said hydration agent and wherein said photopharmaceutical is absorbed into said water matrix.
 3. The apparatus according to claim 2 wherein said cover means includes an internal surface defining a chamber receiving said transparent hydrogel means and wherein said transparent hydrogel means resides in said chamber, and wherein said cover means further comprises a reflective layer provided on said internal surface for reflecting said optical energy through said transparent hydrogel means and to said photopharmaceutical.
 4. The apparatus according to claim 2 wherein said source of optical energy is a laser providing laser light; wherein said optical energy delivery means comprise an array of parallel optical fibers for emitting said laser light from sides thereof, wherein said cover means is provided with an internal reflective surface for reflecting said laser light through said transparent coupling means, and said hydrated stratum corneum into the dermal treatment site, and wherein said transparent hydrogel means is comprised of castable transparent hydrogel and wherein said hydrogel is cast into intimate physical and optical engagement with said array of parallel optical fibers.
 5. The apparatus according to claim 4 wherein said photopharmaceutical is photoactivateable at a predetermined wavelength and wherein said laser provides monochromatic light at said predetermined wavelength through said array of parallel optical fibers.
 6. The apparatus according to claim 5 wherein said laser provides said monochromatic light at a wavelength of 635 nm.
 7. The apparatus according to claim 4 wherein said transparent hydrogel means comprise a first layer of hydrogel received in said chamber and a second layer of hydrogel received in said chamber and for residing intermediate said first layer of hydrogel and the dermal treatment site, said first layer of hydrogel including a water matrix providing said hydration agent and said second layer of hydrogel being smaller in size than said first layer and generally shaped to cover only the dermal lesion located at the dermal treatment site, and said second layer of hydrogel including a water matrix into which said photopharmaceutical is absorbed.
 8. The apparatus according to claim 2 wherein said sealing means comprises a lower portion provided on said cover means which lower portion includes an outwardly extending peripheral portion circumscribing said lower portion and a layer of adhesive applied to said peripheral portion for sealingly engaging the skin to seal said cover means to the skin over the dermal treatment site.
 9. The apparatus according to claim 1 wherein said control means includes a power supply for providing power to said source of optical energy, wherein said control means includes computer means including a programmed logic array under the control of a patient receiving the photodynamic therapy, said computer means connected to said power supply to permit said patient to control the amount of power supplied to said laser and the time said power supply supplies power to said laser to thereby permit the patient to control and vary the photodynamic therapy applied to the dermal lesion. 